Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Strategies to prevent hyperglycemia-induced cytotoxic reactive oxygen species in the retina include the prevention of free radical production, activation of radical-scavenging capacities and inhibition of aldose reductase. This study examined the effect of the standardized Japanese herbal extract product gosha-jinki-gan (GJG) in comparison to insulin treatment in the rat retina. Diabetes was induced in male Wistar rats by single injection of streptozotocin (50 mg/kg i.p.). At 6 and 12 weeks, eye-cups were removed for immunohistochemistry. At 12 weeks, lipid peroxidation (tested with the antiacrolein antibody, Ab5F6) was enhanced significantly in the untreated diabetic group. This effect was absent in both treatment groups, notably in the outer retina. A similar result was obtained for nitrotyrosine overproduction. As an early treatment effect, GJG -- but not insulin -- enhanced soluble guanylate cyclase (sGC) activation (using the function-sensing antibody, MoAb 3221). GJG not only reduces nitroxidative stress and lipid peroxidation in the retina, it also ameliorates glucose metabolism within the cells. We propose that the high glucose turnover in the insulin-treated model disturbs the intracellular redox equilibrium, one result of which might be the impaired sGC activation.
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PMID:Maintaining the redox-balance intact: gosha-jinki-gan but not insulin activates retinal soluble guanylate cyclase in diabetic rats. 1637 52

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.
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PMID:Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. 1684 11

Uncontrolled diabetes mellitus (DM) adversely affects oocyte maturation and embryo development via mechanisms that are yet unclear. Nonetheless, DM may cause uncoupling of nitric oxide synthases (NOSs) with reduction in the bioavailability of nitric oxide (NO), which is critical to maintain oocyte viability and prevent aging. The current study investigates the role of NO-mediated signaling related to oocyte aging in diabetic and nondiabetic mice. Age-related alterations in the oocytes, including ooplasmic microtubule dynamics (OMD), cortical granule (CG) status, and zona pellucida (ZP) hardening as well as the integrity of the spindle/chromatin were studied using confocal microscopy. Oocytes obtained from diabetic mice exhibited accelerated aging compared to that from nondiabetic mice. Moreover, oocytes from diabetic animals were exquisitely sensitive to NOS and guanylate cyclase (GC) inhibitors (L-NAME, ODQ), which induced aging and relatively resistant to its delay by the cGMP derivative (8-Br-cGMP). Oocytes from nondiabetic control mice displayed similar sensitivity to L-NAME in older oocytes, although to a significantly lower extent than that of DM (P < 0.04-0.0001). Despite the differences in response between DM and nonDM mice, the activation of cGMP pathway is essential to maintain the integrity of oocytes and delay oocyte aging. These findings not only indicate the role of NO signaling in the prevention of oocyte aging but also suggest enhanced aging and NO insufficiency in oocytes from diabetic mice. A comprehensive model incorporating our current findings with NOS, GC, and G kinase cycles is presented.
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PMID:Activation of the cGMP signaling pathway is essential in delaying oocyte aging in diabetes mellitus. 1698 97

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.
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PMID:Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide. 1718 32

Our previous studies demonstrated that light-induced vascular relaxation (photorelaxation) was mediated by a tissue source of nitric oxide that was independent of endothelial nitric oxide synthase (eNOS), but sensitive to inhibitors of soluble guanylate cyclase, extracellular nitric oxide scavengers and possessed the properties of a nitrosothiol. In the present study we describe High Performance Liquid Chromatography and spectrofluorometric techniques that allowed us to measure tissue levels of the nitrosothiol, S-nitrosoglutathione and its modulation in mouse aortic tissues, smooth muscle cells and human umbilical vein endothelial cells (HUVECs) following exposure to exogenous S-nitrosoglutathione, light and chemical stimuli. Basal levels of S-nitrosoglutathione were similar in control mouse aortae and HUVECs and the store size could be enhanced by exposure of tissues/cells to nitric oxide solution. No basal S-nitrosoglutathione was detected in tissue from diabetic db/db mice; however, ultraviolet light was still able to elicit relaxation of aortic tissues. Ultraviolet light induced the release of nitric oxide from the S-nitrosoglutathione store with an associated increase in the concentration of nitrite. The release of nitric oxide from the store in HUVECs was modulated by extracellular oxidative stress induced by xanthine/xanthine oxidase and also, in an atropine-sensitive process, by acetylcholine, as well as by the calcium ionophore, ionomycin. These interventions resulted in a reduced S-nitrosoglutathione store and elevated levels of nitrite. These data suggest that endothelial and vascular smooth muscle cells possess stores of nitric oxide that, in part, exist in the form of S-nitrosoglutathione. Furthermore, these stores, albeit small, may provide an additional mechanism for the regulation of vascular tone, especially under conditions, such as diabetes, in which nitric oxide generation or bioavailability is compromised; however, additional studies are required to determine not only whether there are additional chemical storage forms of nitric oxide, but also the location of such stores.
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PMID:Nitrosothiol stores in vascular tissue: modulation by ultraviolet light, acetylcholine and ionomycin. 1729 50

The dysdifferentiation of beta cells in type 2 diabetes appears to be caused and maintained by a vicious cycle of glucolipotoxicity: chronic elevations of glucose and free fatty acids induce beta cell dysdifferentiation as well as apoptosis; the resulting failure of glucose-stimulated insulin secretion tends to maintain the elevations of glucose and free fatty acids. Since extended fasts restore normoglycemia in diabetics, the resulting relief from glucotoxicity has been associated with a marked improvement in beta cell function that can be conserved after the fast if the factors precipitating diabetes--obesity, fatty and high-glycemic-index diets, sedentary lifestyle--have been adequately addressed. The new drug exenatide, an analog of the incretin hormone glucagon-like peptide-1, may be a worthwhile adjuvant to such fasting therapy, since it tends to counteract the glucolipotoxicity-induced down-regulation of the crucially important beta cell transcription factor IDX-1. Exenatide also exerts trophic effects on beta cell mass that in the longer term might help to restore diminished beta cell mass. Supraphysiological concentrations of biotin, possibly because they activate the soluble guanylate cyclase, also promote induction of IDX-1 and counteract the adverse impact of glucolipotoxicity in this regard; thus, high-dose biotin, which is well tolerated, may represent an additional adjuvant for therapeutic fasting intended to normalize beta cell function in type 2 diabetics.
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PMID:Exenatide and biotin in conjunction with a protein-sparing fast for normalization of beta cell function in type 2 diabetics. 1729 59

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.
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PMID:Physiological regulation of penile arteries and veins. 1763 89

Angiotensin converting enzyme (ACE) inhibitors usually cause severe coughing and intolerance while antagonists for angiotensin AT(1) receptor do not stimulate the production of nitric oxide (NO). NO has been shown to regulate arterial hypertension and insulin resistance. Hence, new hybrids of antagonist for angiotensin AT(1) receptor and a NO donor may have potent anti-hypertensive effect and regulate glucose metabolism and insulin resistance. Herein, the effects of [6-(nitrooxymethyl)pyridin-2-yl] methyl 4'-[1-(1,7'-dimethyl-2'-propyl-1H,3'H-2,5'-bibenzo[d]imidazol-3'-yl)ethyl] biphenyl-2-carboxylate (WB1106), a novel NO-releasing derivative of telmisartan newly synthesized, on the vasocontraction, hypertension and diet-induced insulin resistance were examined in vitro using rat aortic strips and in normotensive and spontaneous hypertension rats (SHR rats). Apparently, WB1106 induced the vasorelaxation of contracted rat aortic strips in a dose- and time-dependent manner, which depended on the activity of guanylate cyclase, a characteristic of NO-related function. Furthermore, WB1106 reduced the contractile and blood pressure responses to angiotensin II, which relied on the release of telmisartan. Moreover, treatment with WB1106 significantly reduced the blood pressure with similar potency to telmitarsan and increased the contents of cGMP in SHR rats. Therefore, WB1106 possesses both the angiotensin AT(1) receptor antagonist activity of telmisartan and the NO-releasing property of a 'slow NO donor'. Importantly, in contrast to equimolar telmisartan, treatment with WB1106 significantly attenuated body weight gains and improved glucose tolerance in high-fat and carbohydrate-fed rats, reflecting a synergistic effect of NO and telmisartan. Potentially, WB1106 may be a potent anti-hypertensive drug for treatment of hypertension and diabetes-related cardiovascular diseases in the clinic.
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PMID:WB1106, a novel nitric oxide-releasing derivative of telmisartan, inhibits hypertension and improves glucose metabolism in rats. 1782 96

1. The present study evaluated the effect of diabetes, hypercholesterolaemia and their combination on the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to relaxation of rat isolated aortic rings and the potential contribution of oxidant stress to the disturbance of endothelial function. 2. Thoracic aortic rings from control, diabetic, hypercholesterolaemic and diabetic plus hypercholesterolaemic rats were suspended in organ baths for tension recording. Generation of superoxide by the aorta was measured using lucigenin-enhanced chemiluminescence. 3. The maximal response to acetylcholine (ACh) was significantly reduced in diabetic or hypercholesterolaemic rats compared with control rats. In rats with diabetes plus hypercholesterolaemia, both the sensitivity and maximal response to ACh was impaired. In control rats, the response to ACh was abolished by the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) or inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, in rats with diabetes, hypercholesterolaemia or both, relaxation to ACh was resistant to inhibition by L-NNA or ODQ, but abolished by additional inhibition of K(Ca) channels with charybdotoxin plus apamin. 4. The generation of superoxide was not significantly enhanced in aortic rings from either diabetic or hypercholesterolaemic rats, but was significantly increased in aortic rings from rats with diabetes plus hypercholesterolaemia. 5. These results suggest that when diabetes and hypercholesterolaemia impair endothelium-dependent relaxation, due to a diminished contribution from NO, a compensatory contribution of EDHF to endothelium-dependent relaxation of the aorta is revealed. The attenuation of NO-mediated relaxation, at least in the presence of both diabetes and hypercholesterolaemia, is associated with enhanced superoxide generation.
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PMID:Type 1 diabetes and hypercholesterolaemia reveal the contribution of endothelium-derived hyperpolarizing factor to endothelium-dependent relaxation of the rat aorta. 1794 94

Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
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PMID:Prostacyclin among prostanoids. 1827 80


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